Abstract
The envelope glycoproteins (Env) of human and simian immunodeficiency viruses (HIV and SIV, respectively) mediate virus binding to the cell surface receptor CD4 on target cells to initiate infection1. Env is a heterodimer of a transmembrane glycoprotein (gp41) and a surface glycoprotein (gp120), and forms trimers on the surface of the viral membrane. Using cryo-electron tomography combined with three-dimensional image classification and averaging, we report the three-dimensional structures of trimeric Env displayed on native HIV-1 in the unliganded state, in complex with the broadly neutralizing antibody b12 and in a ternary complex with CD4 and the 17b antibody. By fitting the known crystal structures2,3 of the monomeric gp120 core in the b12- and CD4/17b-bound conformations into the density maps derived by electron tomography, we derive molecular models for the native HIV-1 gp120 trimer in unliganded and CD4-bound states. We demonstrate that CD4 binding results in a major reorganization of the Env trimer, causing an outward rotation and displacement of each gp120 monomer. This appears to be coupled with a rearrangement of the gp41 region along the central axis of the trimer, leading to closer contact between the viral and target cell membranes. Our findings elucidate the structure and conformational changes of trimeric HIV-1 gp120 relevant to antibody neutralization and attachment to target cells.
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Acknowledgements
We thank J. Bess and J. Lifson for providing purified, AT-2 treated HIV-1 BaL virus; P. Kwong for providing purified preparations of Fab fragments of the neutralizing antibodies b12 and 17b; S. Fellini and colleagues for assistance with use of the high-performance computational capabilities of the Biowulf Linux cluster at the National Institutes of Health, Bethesda, Maryland (http://biowulf.nih.gov); E. Tyler for assistance with figures; T. M. Chou for assistance with microscope maintenance; and A. Bennett, J. Milne and T. White for comments on the manuscript. This work was supported by funds from the intramural programme of the National Cancer Institute (to S.S.), and from the National Science Foundation and the Department of Defense (to G.S.).
Author information
Jun Liu, Alberto Bartesaghi and Mario J. Borgnia: These authors contributed equally to this work.
Authors and Affiliations
Laboratory of Cell Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA ,
Jun Liu, Alberto Bartesaghi, Mario J. Borgnia & Sriram Subramaniam
Department of Electrical and Computer Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA,
Guillermo Sapiro
- Jun Liu
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- Alberto Bartesaghi
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- Mario J. Borgnia
Search author on:PubMed Google Scholar
- Guillermo Sapiro
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- Sriram Subramaniam
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Correspondence to Sriram Subramaniam.
Supplementary information
Supplementary Information 1 (download PDF )
The file contains Supplementary Figures S1-S7 and Legends. (PDF 5432 kb)
Supplementary Information 2 (download MOV )
The file contains Supplementary Movie 1. The movie shows density map of unliganded HIV-1 spike determined by cryo-electron tomography combined with 3D averaging. The density includes contributions from three gp120 and three gp41 molecules. The coordinates of monomeric gp120 as determined in the complexe with CD4 and the X5 antibody (2B4C coordinates) are shown docked into the map, highlighting the location of the V3 loop regions at the top of the spike. (MOV 4563 kb)
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Liu, J., Bartesaghi, A., Borgnia, M. et al. Molecular architecture of native HIV-1 gp120 trimers. Nature 455, 109–113 (2008). https://doi.org/10.1038/nature07159
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DOI: https://doi.org/10.1038/nature07159
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